Cancer Stem Cell Markers in Squamous Cell Carcinomas of the Salivary Glands.

BACKGROUND: Cancer stem cells (CSC) are cells that exhibit stem cell properties and are pivotal in tumor biology. CSC markers have been described for many tumorous entities. However, to this date, there is no data on CSC markers in respect to squamous cell carcinomas (SCC) of the salivary glands. METHODS: Histologic samples from patients with salivary gland SCCs were stained for CSC markers (ALDH-1/BMI-1/SOX-2/CD-44/vimentin) and divided into high and low expression subgroups. These were then correlated with tumor and patient characteristics as well as overall survival (OS), disease-specific survival, recurrence-free survival and local control rates (LCR) after 3 and 5 years. RESULTS: Overall, 31 samples were included. CD-44 and ALDH-1 expression were associated with tumor origin (metastatic/primary disease, p = 0.048 and p = 0.011, respectively). Strong BMI-1 expression was associated with poorer OS (62.9 vs. 27.3%, p = 0.029), strong SOX-2 expression was associated with poorer LCR (62.5 vs. 21.9%, p = 0.007). CONCLUSION: CD-44 and ALDH-1 may be useful in differentiating between primary SCCs and metastatic disease. BMI-1 and SOX-2 are correlated with poorer prognosis.

Coexistence of the BRCA1 and KRAS mutations in a patient with salivary gland carcinoma arising in mediastinal mature teratoma.

Teratoma with malignant transformation is a rare type of malignant teratoma. In the present case, we describe a patient with salivary gland carcinoma (SGC) generating in mediastinal mature teratoma. Next-generation sequencing showed BRCA1 and KRAS somatic mutations, which might be associated with malignant transformation of the mediastinal mature teratomas. To our knowledge, the present case is the first report of coexistence of BRCA1 and KRAS mutations in mature cystic teratoma with malignant transformation to SGC. And the tumor showed a good response to chemotherapy with cisplatin and paclitaxel according to the transformed histology.

Immunohistochemical Reactivity of Prostate-Specific Markers for Salivary Duct Carcinoma.

OBJECTIVES: NKX3.1, a transcription factor related to androgen expression, has recently been introduced as a diagnostic marker of prostate adenocarcinoma. Salivary duct carcinoma (SDC) is typically positive for androgen receptor (AR). Therefore, we hypothesized that NKX3.1 is a new immunohistochemical marker for SDC and aimed to investigate whether NKX3.1 staining in combination with other immunomarkers of prostate carcinoma could have a diagnostic or prognostic value in SDC. METHODS: Materials obtained from 42 resected SDCs were examined by immunohistochemistry using antibodies against AR, NKX3.1, α-methylacyl-CoA racemase (AMACR), prostatic acid phosphatase (PAP), and prostate-specific antigen (PSA). RESULTS: In immunoreactivity among SDC cases, 81.0, 35.7, 58.5, 33.3, and 0% were positive for AR, NKX3.1, AMACR, PAP, and PSA, respectively. AMACR and PAP immunoreactivity rates were higher in recurrence cases than in cases with no recurrence. CONCLUSIONS: NKX3.1 expression is useful for SDC diagnosis, but decreased NKX3.1 expression was not correlated with SDC progression. The immunoreactivity of AMACR and PAP could be useful for assessing prognosis in SDC, but immunohistochemical staining of prostate-specific markers should be interpreted with caution when determining whether a metastatic tumor is of prostate origin, especially when patients have a history of SDC.

Successful multimodal treatment of intraoral salivary duct carcinoma in a patient with multiple lymph node metastases: a case report.

BACKGROUND: Salivary duct carcinoma (SDC) is a high-grade salivary gland malignancy that is associated with an aggressive clinical behavior and poor prognosis. Herein, we report on a long surviving case of SDC of the minor salivary gland with multiple lymph node metastases (LNMs). CASE PRESENTATION: An 83-year-old woman presented with a history of lymphadenopathy in the right side of the neck and recent onset and rapid growth of a mass in the right buccal region. Clinical examinations and biopsy findings were suggestive of a salivary gland malignant tumor with regional LNMs. The patient was treated with neoadjuvant chemotherapy. Tumor excision and ipsilateral radical neck dissection were performed, followed by adjuvant chemoradiotherapy. Postoperative histological examination revealed a tumor with irregular nests of atypical ductal epithelial cells, a cribriform growth pattern, and comedo-like central necrosis that lead to a final diagnosis of SDC. LNMs were observed in six lymph nodes of the right side of the neck. The patient underwent postoperative chemotherapy using single-agent cisplatin that was administered concurrently with radiotherapy (total, 65 Gy). There was no evidence of local recurrence or distant metastasis for >6 years. CONCLUSIONS: Although available data on treatment modalities for SDC remain limited, multimodal therapy may contribute to improved clinical outcomes in patients with advanced intraoral SDC.

Renal clear cell carcinoma metastasis to salivary glands - a series of 9 cases: clinico-pathological study.

Metastatic tumors involving salivary glands arising from the non-head and neck area are very rare. Renal cell carcinoma (RCC) is known for its high propensity for metastasis to unusual localizations. RCC metastasis to the maxillofacial area is an uncommon event (16%), but metastasis to salivary glands is extremely rare. We report a series of 9 such cases retrieved from two institutions. The group included 6 females and 3 males. The age at diagnosis ranged from 60 to 97 years (mean 72.6 years). The tumors involved the parotid gland in 7 cases, and the submandibular and small salivary gland of the oral cavity in 1 case each. The size of tumors ranged from 0.4 to 5 cm. Total parotidectomy with selective neck dissection was performed in 4 cases, while superficial parotidectomy was performed in 1 case and simple resection in 3 cases. Histologically, all the tumors were clear cell renal cell carcinomas, and therefore the differential diagnosis mainly included clear cell variants of salivary gland carcinomas. The parotid gland was the initial manifestation of renal malignancy in 4 of the cases, while in the remaining 5 cases a history of RCC had been known. The salivary gland involvement developed from 11 months to 13 years after the time of diagnosis of the primary tumor. In 2 cases it was the first site of dissemination. Pathologists need to maintain a high index of suspicion for the possibility of metastasis when confronted with oncocytic or clear cell neoplasms developing in salivary glands. RCC, although rare, should be included in this differential diagnosis.

[Clinical investigation on distant metastases of salivary gland carcinoma after being treated by surgery combined with 125I internal brachytherapy].

OBJECTIVE: To investigate clinical features of distant metastases (DM) and analyze clinicopathologic risk factors associated with DM from salivary gland carcinomas after being treated by surgery combined with 125I internal brachytherapy. METHODS: Between October 2001 and March 2010, 197 patients with salivary gland carcinoma were treated by surgery combined with 125I internal brachytherapy and had follow-up for 2 years or more. Univariate and multivariate analyses were performed to evaluate clinicopathologic risk factors that might influence the risk of distant metastases. RESULTS: DM occurred in 28 of 197 patients (14.2%). The commonest site of distant metastases overall was the lung 89.3% (25/28), followed by bones 17.9% (5/28) and liver (4/28). DM developed after an average interval of (44.2±45.8) months from the time of initial diagnosis, and the mean interval was 64 months. The average time to death after the diagnosis of DM was only (9.7±13.4) months, and the mean time was 12 months. The 3-year locoregional control rate and survival rate were 90.8%, and 87.8% respectively,and the 5-year ones 84.0% and 81.0%, respectively. Univariate analyses revealed that the risk of distant metastases was significantly influenced by locoregional tumor failure (F=26.997, P<0.01) and histologic differentiation (F=1.592, P<0.01). Multivariate analysis of freedom from distant metastases revealed that locoregional control (F=29.332, P<0.01) significantly influenced this end point. CONCLUSION: Salivary gland carcinoma could achieve high local control rate after being treated by surgery combined with 125I internal brachytherapy, and the average interval from diagnosis to DM was prolonged, DM was significantly influenced bylocoregional control.

Maxillofacial metastases: a retrospective review of one institution's 15-year experience.

PURPOSE: Metastasis to the maxillofacial region is a rare occurrence. In our retrospective study of patients with metastasis to the maxillofacial region, the subjects were evaluated to define the clinical behavior patterns in response to the treatment given. MATERIALS AND METHODS: A retrospective record review during a 15-year period (1990 to 2005) was conducted. The patients were selected for inclusion in the present study if they had histologically confirmed maxillofacial metastases. RESULTS: In our retrospective study, during the 15-year period, 1,221 new patients with maxillofacial/oral cancer were seen and evaluated. Of these 1,221 patients, 26 (16 men and 10 women) were identified as having a histologically confirmed metastasis to the maxillofacial region, for an incidence of 2.1%. CONCLUSIONS: Patients with metastasis to the maxillofacial region are often deemed to not be surgical candidates because of the extensive nature of the metastatic disease. We believe that surgical intervention plays a beneficial role in improving quality of life in a properly selected group of patients with metastasis to the maxillofacial region. In our case series, surgery was performed in about 50% of the patients, and palliation and radiotherapy were the most commonly used modalities.

Primary cutaneous adenoid cystic carcinoma: an unusual case.

Primary cutaneous adenoid cystic carcinoma (PCACC) is an uncommon adnexal skin tumor. It is usually located on the head or neck of people over 50 years of age, affecting men and women equally. The etiology is unclear; the source used to be considered the eccrine glands, but more recent hypotheses defend this carcinoma as originating in the apocrine glands or modified apocrine glands. The tumor may clinically appear as a normal skin-colored nodule with ill-defined edges and slow growth. Histologically, a proliferation of neoplastic cells appears, which could present in a tubular, cribriform, or solid pattern. Perineural invasion is characteristic for this tumor. For diagnosis of PCACC it is essential to exclude metastasis, especially in the salivary glands. Treatment involves surgical excision. We present a case of primary adenoid cystic carcinoma in a young woman located on the skin of the upper limb, which is an unusual place.

Cribriform adenocarcinoma of the tongue.

We report a case of a 73-year-old female with a tumour of the tongue, operated with two relapses. A single metastasis to the lymph node was present. Currently, the patient is alive without evidence of disease. The histological diagnosis of cribriform adenocarcinoma of the tongue was rendered. The differential diagnosis of adenocarcinomas of the tongue is discussed.

MCM3 proliferative index is worthier over Ki-67 in the characterization of salivary gland tumors.

BACKGROUND: Salivary gland tumors bear uncanny characteristics of being different based on their morphological aspects rather than the presence of clear demarcation. This ambiguity in the spectrum from benign to malignant salivary gland neoplasms while categorizing the neoplasm is having inherent pitfalls. The present study was, therefore, designed to characterize benign and malignant salivary gland tumors based on their proliferative indices. MATERIALS AND METHOD: Study samples comprised of 97 cases of histopathologically confirmed benign and malignant salivary gland tumors. The cases were immunohistochemically assessed for MCM3 and Ki-67 expressions and the molecular characterization was performed based on the findings. RESULTS: The majority of benign and malignant salivary gland tumors were from the parotid gland, (51.2%) and (42.4%), respectively. Overall mean labeling index of MCM3 was higher i.e., (5.60 ± 3.99) in comparison to Ki-67 i.e., (2.82 ± 3.14) with P = 0.05 using paired t-test. Besides, malignant salivary gland neoplasms represented a higher mean score of MCM3 and Ki-67 than benign neoplasms. CONCLUSION: The requirement of a novel marker has led to the use of MCM3 which has a characteristic role in the entire spectrum of the cell cycle. The present study highlighted the extrapolation of MCM3 over Ki-67 for diagnosis and for true characterization of biologic behavior of salivary gland pathologies which may, in turn, influence the treatment modality employed for such lesions.

Metastasis of small cell bronchopulmonary cancer in the submandibular gland: a new case.

The metastases of bronchopulmonary cancer in the submandibular gland are infrequent. We report a case of metastasis in the submandibular gland in a patient with small cell lung cancer who had chemotherapy with disease stability.

Identification of c-kit gene mutations in primary adenoid cystic carcinoma of the salivary gland.

The CD117 (KIT) protein is overexpressed in many human neoplasms including adenoid cystic carcinoma of salivary glands. To evaluate the function of c-kit-activating mutations in adenoid cystic carcinoma of the salivary gland, we studied 14 cases (13 primary, 1 cervical lymph node metastasis) from our institution. KIT protein expression was evaluated by immunohistochemistry using formalin-fixed paraffin-embedded tissue. Mutational analyses of c-kit extracellular (exon 9), juxtamembrane (exon 11) and tyrosine kinase domains (exons 13 and 17) were performed by polymerase chain reaction, clonal selection and DNA sequencing. All 14 cases demonstrated strong KIT expression by immunohistochemistry. Molecular analysis was successful in 8 of 14 cases, and c-kit missense point mutations were detected in seven of eight cases (88%) including seven in exon 11, two in exon 9, two in exon 13 and two in exon 17. Eight silent point mutations were detected in five cases. Two cases contained missense mutations in more than one exon. Different mutations were found in the primary tumor and the cervical lymph node metastasis of one patient. Point mutations in domains similar to those described in gastrointestinal stromal tumors were detected, including Pro551Leu and Lys558Glu (5' end of exon 11), Leu576Phe (3' end of exon 11), Val643Ala (exon 13) and Asn822Ser (exon 17). Additional novel point mutations in exons 9, 11, 13 and 17 were also identified. This study is the first to report c-kit gene mutations in primary adenoid cystic carcinoma of the salivary gland. Identification of such potential gain-of-function mutations in exon 11, and less frequently in exons 9, 13 and 17, suggests that KIT may be involved in the pathogenesis of adenoid cystic carcinoma of salivary glands. Our study raises a prospect of correlation of c-kit mutation and a potential treatment of adenoid cystic carcinoma with tyrosine kinase inhibitor (imatinib).

Establishment and characterization of pleomorphic adenoma cell systems: an in-vitro demonstration of carcinomas arising secondarily from adenomas in the salivary gland.

BACKGROUND: Among the salivary gland carcinomas, carcinoma in pleomorphic adenoma has been regarded as a representative carcinoma type which arises secondarily in the background of a pre-existent benign pleomorphic adenoma. It is still poorly understood how and which benign pleomorphic adenoma cells transform into its malignant form, carcinoma ex pleomorphic adenoma. METHODS: We have established five cell systems from a benign pleomorphic adenoma of the parotid gland of a 61-year-old woman. They were characterized by immunofluorescence, classical cytogenetics, p53 gene mutational analysis, fluorescence in-situ hybridization, and histopathological and immunohistochemical examinations of their xenografts, to demonstrate their potency of secondary transformation. RESULTS: We established and characterized five cell systems (designated as SM-AP1 to SM-AP5) from a benign pleomorphic adenoma of the parotid gland. SM-AP1 to SM-AP3 showed polygonal cell shapes while SM-AP4 and SM-AP5 were spindle-shaped. SM-AP1-3 cells were immunopositive for keratin only, indicating their duct-epithelial or squamous cell differentiation, while SM-AP4/5 cells were positive for both keratin and S-100 protein, indicating their myoepithelial cell differentiation. Chromosome analyses showed numeral abnormalities such as 5n ploidies and various kinds of structural abnormalities, such as deletions, translocations, derivatives and isodicentric chromosomes. Among them, der(9)t(9;13)(p13.3;q12.3) was shared by all five of the cell systems. In addition, they all had a common deletion of the last base G of codon 249 (AGG to AG_) of the p53 gene, which resulted in generation of its nonsense gene product. Transplanted cells in nude mice formed subcutaneous tumors, which had histological features of squamous cell carcinoma with apparent keratinizing tendencies. In addition, they had ductal arrangements or plasmacytoid appearances of tumor cells and myxoid or hyaline stromata, indicating some characteristics of pleomorphic adenoma. CONCLUSION: This study demonstrates in vitro that certain cell types from pleomorphic adenoma are able to clone and survive over a long term and develop subcutaneous tumors in nude mice. The histological features of squamous cell carcinoma from the transplanted cell systems in nude mice might suggest a secondary onset of malignancy from a pre-existing benign adenoma.

Response to oxaliplatin with cetuximab in minor salivary gland adenoid cystic carcinoma.

Esophageal localization of adenoid cystic carcinoma of minor salivary glands is rare; it may occur in the early to mid-sixties' age group and is more frequently encountered in men than women. In the majority of cases, it arises from subepithelial glands of the middle to lower third of the esophagus, a similar distribution as squamous cell carcinoma. Prognosis depends mostly on tumor staging and resectability, which represents the only chance of cure. Due to the extreme rarity of this condition, there is limited experience with systemic therapy for advanced disease. We report a case of a patient with metastatic primary esophageal adenoid cystic carcinoma progressing on platinum- and irinotecan-based regimens, who achieved an objective response with oxaliplatin-based chemotherapy in combination with cetuximab.

Metastatic hepatocellular carcinoma to the parotid gland: A diagnostic dilemma with review of the literature.

Hepatocellular carcinoma (HCC) is the most common primary hepatic malignancy and is a leading cause of cancer-related death worldwide. It has a very aggressive clinical course, with a mean survival rate of much less than a year if left untreated. Here, we present a case of a 68-year-old male with progressively enlarging painful right facial swelling, involving the ramus and condyle of mandible on contrast-enhanced computed tomography mimicking an osteosarcoma. Eventually, the final diagnosis of HCC metastatic to the right parotid gland was made. We report a case of a rare metastasis of HCC to the parotid gland. Furthermore, the present case demonstrates the importance of tissue biopsy and immunohistochemistry for obtaining an accurate final diagnosis.

Prognostic value of programed death ligand-1 and ligand-2 co-expression in salivary gland carcinomas.

OBJECTIVES: The aim of the present study was to investigate the molecular basis for the use of immune checkpoint inhibitors to treat salivary gland carcinomas (SGC). MATERIALS AND METHODS: We examined the clinical and prognostic significance of programed death ligands 1 and 2 (PD-L1 and -L2) expression using immunohistochemistry and in situ hybridization, as well as microsatellite instability (MSI) status using polymerase chain reaction, along with tumor-infiltrating lymphocytes (TILs) in 30 cases of SGC. RESULTS: The SGC cases studied included adenoid cystic carcinoma (AdCC, 36.7%), salivary duct carcinoma (SDC, 26.7%), mucoepidermoid carcinoma (MEC, 23.3%), and carcinoma ex pleomorphic adenoma (CxPA, 13.3%). Either PD-L1 or PD-L2 overexpression was observed in 36.7% patients. PD-L2 expression was associated with reduced disease-specific survival (DSS) and disease-free survival (DFS) (P = 0.0266 and P = 0.0209, respectively). Simultaneous PD-L1 and PD-L2 overexpression was detected in 13.3% of cases, and was correlated with reduced DSS (P = 0.0113). Among non-AdCCs, all cases that developed distant metastasis were positive for PD-L2 (P = 0.001). Cases showing low-TILs that were positive for either PD-L1 or L2 were associated with poor DFS. No MSI was detected in the SGC cases studied. CONCLUSION: To our knowledge, this is the first comprehensive study examining PD-L1 and PD-L2 status, MSI status, and TILs in SGC. Our results indicate that the PD-1/PD-L1 or PD-L2 pathway, which is associated with poor clinical outcomes, may provide promising therapeutic targets against SGC in selected patients. Further experimental and clinical studies are encouraged.

Extrapancreatic F-18 FDG accumulation in autoimmune pancreatitis.

We report two cases of autoimmune pancreatitis (AIP) in which fluorine-18 fluorodeoxyglucose (FDG) showed moderate accumulation in the pancreas, as well as in bilateral submandibular glands and in multifocal lymph nodes. FDG positron emission tomography (PET)/computed tomography (CT) is a useful diagnostic tool to assess the extrapancreatic lesions of AIP, which is a recently proposed new clinicopathological entity named immunoglobulin G4 (IgG4)-related systemic disease. Recognition of the FDG-PET/CT findings of IgG4-related sclerosing disease is crucial to avoid unnecessary surgery or other intervention because of similarities to malignant lymphoma or malignant tumor with multiple lymph node metastases.

Intraocular metastasis of medullary thyroid carcinoma investigated by transscleral fine-needle aspiration. A case report and review of the literature.

Medullary thyroid carcinoma occurs in a sporadic setting and may also be inherited in an autosomal dominant fashion, which is related with germline mutations of the RET gene. Metastases are often present at the time of a diagnosis-most frequently within the cervical lymph nodes, followed by the liver, lungs, and bones. Intraocular metastases are extremely rare. We present a case of choroidal metastasis as a first presentation of disease progression in a patient with Multiple Endocrine Neoplasia type 2A syndrome (MEN2A) who had undergone thyroidectomy 33 years earlier for medullary thyroid carcinoma. Transscleral aspirate smears showed necrotic malignant cells suggesting amelanotic malignant melanoma or metastatic neuroendocrine tumor. The similar cells were found on parotid fine-needle aspiration. The diagnosis of metastatic medullary thyroid carcinoma was definitely established on the parotidectomy specimen based on its characteristic morphological and immunohistochemical features. This is the only case of ocular metastasis from medullary thyroid carcinoma found in the English literature that was investigated by pathological examination using transscleral fine-needle aspiration biopsy.

Report of a unique case of myoepithelial carcinoma of left parotid gland with metachronous bilateral cavernous sinus metastasis.

Myoepithelial carcinoma (MC) is a rare, locally aggressive malignant neoplasm of the salivary glands. Only few evidences on its metastatic behavior are available in the literature. We herein present a unique case of MC of left parotid gland which metastasized to bilateral cavernous sinuses. The patient was successfully treated with palliative radiotherapy and chemotherapy.